2,4-diamino-5-(3,45-trimethoxybenzyl)-6-arylsulfonylpyrimidines

ABSTRACT

The invention relates to 2,4-diamino-5-(3,4,5-trimethoxybenzyl)6-arylsulfonyloxypyrimidines. These compounds have been found to have bacteriostatic activity similar to that of sulfaphenazole.

United States Patent [191 Gluncic et al.

[ Dec. 17, 1974 2,4-DIAMINO-5-(3,45- TRIMETHOXYBENZYL)-6-ARYLSUL- FONYLPYRIMIDINES Inventors: Berislav Gluncic; Krunoslav Kovacevic, both of Zagreb, Yugoslavia Pliva Pharmaceutical and Chemical Works, Zagreb, Yugoslavia Filed: Sept. 21, 1972 Appl. No.: 290,839

Assignee:

Foreign Application Priority Data Oct. 4, 1971 Yugoslavia 250l/7l U.S. Cl. 260/2565 R, 424/251 Int. Cl C07d 51/42 Field of Search 260/2565 R [56] References Cited UNITED STATES PATENTS 2,673,204 3/1954 Heinrich et al. 260/2564 C 3,663,544 5/1972 .Milzner et al. 260/2564 E OTHER PUBLICATIONS Brown, The Pyrimidines, Interscience, 71-72.

Wagner et al., Synthetic Organic Chemistry, John Wiley & Sons, 1953, pp. 429-431, 599-601, 823.

Primary ExaminerRichard J. Gallagher Attorney, Agent, or Firm-Kurt Kelman 1 Claim, No Drawings 2 ,4-DIAMlNO-5-(3,45-TRIMETHOXYBENZYL )-6- ARYLSULFONYLPYRIMIDINES The invention relates to 2,4-diamino-5-(3,4,5- trimethoxybenzyl)-6-arylsulfonyloxypyrimidines of the general formula:

wherein R represents the radicals H, CH Cl, Br, NHCOCH and NHCOCH CH The compounds are new and have not been described in the literature. These compounds have activity similar to sulfaphenazole, i.e. l-phenyl-S- sulfanilamidopyrazole and show bacteriostatic activity on test strains of Streptococcus haemoliticus in a concentration of 10 mcgs./ml. of nutrient medium and on E. coli and Pseudomonas pyocyanae in a concentration of 250 mcgs./ml. of nutrient medium. Against Staphylococcus pyogerles aureus. activity was noted. in a concentration of 250 megs/ml. of nutrient medium for compounds wherein R represents Br, NHCOCH and NHCOCH CH The testing was effected by dilution test in vitro in a l percent glucose bouillon solution.

1t has been found that the compounds cited above can easily be prepared by condensation of ethyl cyanoacetate and 3,4,5-trimethoxybenzylchloride with sodium hydride as condensation agent. Condensation may be effected by heating at l 10C for 2 hours to prepare ethyl 2-(3,4,5-trimethoxybenzyl)-cyanoacetate. By further condensation of obtained ester with guanidine in dry alcohol, such as ethanol. in the presence of sodium alkoxyde, such as ethoxyde, by heating to boiling during a period of 3 hours and then by evaporating to dryness under lowered pressure, dissolving the residue in water and precipitating with diluted mineral acid, 2.4-diamino-5-(3,4.5-trimethoxybenzyl)-6- hydroxypyrimidine is prepared. ln tautomeric form, this hydroxpyrimidine appears as 2,4-diimino-5-(3,4.5- trimethoxybenzyl)-barbituric acid. By condensation of the prepared hydroxypyrimidine derivative with arylsulphochlorides of the general formula 11:

wherein R has the above meaning. and further by addition of acetone and 1 N sodium hydroxyde solution, so that by adding a further quantity of sodium hydroxyde solution. the pH of the reaction mixture is maintained at 9. compounds of the general formula I are prepared. The reaction is carried out during a period of 3 hours at C when R has the meaning of H, CH and Cl, and during a period of4 hours at 0C when R has the meaning of Br. NHCOCH and NHCOCH CH The process of the present invention is illustrated in greater detail by the following examples.

EXAMPLE 1 To 100 mls. of ethyl cyanoacetate cooled down to 0C. there were added in small portions 4 grs. (0.0834

Mole) of a 50 percent suspension of sodium hydride in mineral oil, and then 18 grs. (0.0831 Mole) of 3,4,5- trimethoxybenzylchloride. The reaction mixture was heated to l 10C and stirred at this temperature for 2 hours. The precipitated sodium chloride was removed by vacuum filtration. The unreacted ethyl cyanoacetate .was distilled err, and the residue was distilled at l-l80C/0.01 mm Hg. A yield of 17.45 grs. (71.7 percent) of pure ethyl 2-(3,4,5-trimethoxybenzyl)- cyanoacetate having a melting point of 37C was obtained.

EXAMPLE 2 To sodium ethoxyde, prepared by dissolving 0.9 grs. (0.039 Mole) of sodium in 15 mls. of dry ethanol, was added a mixture of 2 grs. (0.0162 Mole) of guanidine nitrate and 3.6 grs. (0.0124 Mole) of ethyl 2-(3,4,5- trimethoxybenzyl)-cyanoacetate. The reaction mixture was heated to boiling for 3 hours and then evaporated to dryness under lowered pressure. To the residue was added 15 mls. of water after which it was acidified to pH 4 by adding a 10 percent hydrochloric acid solution. The separated precipitate was recovered by filtration under suction pressure. The recovered filtrate was recrystallized from dry ethanol. Pure 2,4-diamino-5- (3,4,5-trimethoxybenzyl)-6-hydroxypyrimidine of a melting point of 274-275C was obtained.

EXAMPLE 3 A mixture of 3.1 grs. (0.01 Mole) of 2,4-diamino-5- (3,4,5-trimethoxybenzyl )-6-hydroxypyrimidine, l6 mls. of 1 N sodium hydroxyde, 1.9 grs. (0.011 Mole) of benzenesulphochloride, and 10 mls. of acetone was stirred for 3 hours at 25C. During the reaction, the pH of the reaction mixture was maintained at pH 9 by adding 1 N sodium hydroxyde solution. The separated colourless precipitate was recovered by filtration under suction pressure and recrystallized from 96 percent ethanol. Pure 2,4-diamino-5-(3,4,5-trimethoxybenzyl)- o-benzenesulphonyloxypyrimidine of having a melting point of 222223C was obtained.

EXAMPLE 4 The procedure according to the process described in Example 3 was repeated except that from ptoluenesulphochloride there was obtained 2,4-diamino- 5-(3,4,5-trimethoxybenzyl)-6-ptoluenesulphonyloxypyrimidine having a melting point of 206-208C.

EXAMPLE 5 The procedure according to the process described in Example 3 was repeated except that from p-chlorobenzenesulphochloride there was obtained 2,4-diamino-5- (3.4,5-trimethoxybenzyl)-6-p-chlorobenzenesulphonyloxypyrimidine of having a melting point of 206208C.

EXAMPLE 6 The procedure according to the process described in Example 3 was repeated except that from p-bromobenzenesulphonylchloride by carrying out the reaction during a period of 4 hours at 0C, there was obtained 2,4-diamino-5-(3,4.5-trimeth0xybenzyl)-6-pbromobenzenesulphonyloxypyrimidine having a melting point of 203C.

EXAMPLE 7 The procedure according to the process described in Example 6 was repeated except that from pacetamidobenzenesulphochloride there was obtained 2,4-diamino--(3,4,5-trimethoxybenzyl)-6-pacetamidobenzenesulphonyloxypyrimidine melting point of 206207C.

EXAMPLE 8 having a What we claim is: l. 2,4-Diamino-5-(3,4,5-trimethoxybenzyl)-6-arylsulphonyloxypyrimidines of the formula:

wherein R is a radical of the group consisting of H, CH Cl, Br, NHCOCH; and NHCOCH CH v 

1. 2,4-DIAMINO-5-(3,4,5-TRIMETHOXYBENZYL)-6ARYSULPHONYLOXYPRIMIDINES OF THE FORMULA: 